International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

I3 Genetic Analysis of Deafness - Screening for New Mouse Deafness Mutations and Their Modifiers

R. Hardisty1, A. Kiernan2, A. Erven2, D. Saw1, P. Mburu1, A. Varela1, J. Peters1, P. Nolan1, S. Voegeling3, J. L. Guenet3, J. Hunter4, K. P. Steel2 and S. D. M. Brown1. 1MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, OX11 ORD, UK; 2MRC Institute of Hearing Research, Nottingham NG7 2RD, UK; 3Institut Pasteur, Paris, France; 4SmithKline Beecham Pharmaceuticals, Harlow, CM19 5AW, UK

The bulk of genetic deafness in the human population is non-syndromic caused by sensorineural defects in the inner ear neuroepithelium, the organ of Corti. A large number of mouse deaf mutants are available, many carrying neuroepithelial defects. However, despite this apparently large catalogue, mouse models for many human deafness loci are not available. We have embarked upon a major mouse mutagenesis programme to recover a large number of novel mutant phenotypes, including new mouse deaf mutants. As part of our genome-wide screen for dominant mutations, we have incorporated tests for auditory and vestibular function, including a click-box emitting a high frequency soundburst to test for deafness as well as balance tests to assess vestibular function. From 10,000 mice screened to date 29 phenotypes with vestibular and/or hearing anomalies have been detected, and a number subjected to inheritance testing. Of the proven mutants there are 9 with vestibular dysfunction, 1 mouse with vestibular and hearing deficits, and 2 mice with severe hearing impairment alone. Of the 9 vestibular mutations, 5 map to proximal chromosome 4 in the vicinity of the Wheels locus, a dominant mutation demonstrating circling behaviour and a circadian rhythm phenotype. Morphological studies indicate that these mutations have a truncation of the lateral semi-circular canal. All five mutants were derived from different mutagenised males and appear to represent new alleles at the Wheels locus. We have also employed mutagenesis in sensitised screens to identify modifiers involved in known auditory transduction pathways. Shaker1 (sh1), a recessive deafness mutation in the mouse, encodes myosin VIIA which appears to function in stereocilia positioning at the apical hair cell surface in the neuroepithelia. To identify modifiers of the sh1 locus, mutagenised males are mated to sh1 heterozygote females and F1 offspring screened for auditory and vestibular anomalies. Progeny testing of affected F1s distinguishes between new dominant deafness mutations, new sh1 alleles and dominant enhancers of the sh1 mutation. Currently, 1,000 F1 progeny have been analysed and several potential mutants are undergoing progeny testing. Both direct and modifier screens will enhance our knowledge of the panoply of genes involved in auditory system function.

 


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